“On-water” synthesis of quinazolinones and dihydroquinazolinones starting from O-bromobenzonitrile

Article abstract of DOI:10.3390/molecules23092325

A versatile and practical “on-water” protocol was newly developed to synthesize quinazolinones using o-bromobenzonitrile as a novel starting material. Studies have found that air as well as water plays an important role in synthesis of quinazolinones. Further investigation indicated that dihydroquinazolinones can be prepared with this protocol under the protection of N₂. The protocol can be extended to other substrates and various quinazolinones and dihydroquinazolinones were obtained. o-Bromobenzamide, o-aminobenzonitrile, and o-aminobenzamide were also evaluated as starting materials, and the results further proved the versatility of this protocol, especially towards dihydroquinazolinones.

Full text of DOI:10.3390/molecules23092325

molecules
Article
“On-Water” Synthesis of Quinazolinones and
Dihydroquinazolinones Starting from
o-Bromobenzonitrile
Zibin Liu † , Li-Yan Zeng †, Chao Li, Fubiao Yang, Fensheng Qiu, Shuwen Liu * and
Baomin Xi *
Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences,
Southern Medical University, Guangzhou 510515, China; liuzibin1007@126.com (Z.L.);
Zengly2011@hotmail.com (L.-Y.Z.); LC151820cg@126.com (C.L.); 15625123630@163.com (F.Y.);
qiufensheng1996@163.com (F.Q.)
* Correspondence: liusw@smu.edu.cn (S.L.); xibaomin@sohu.com (B.X.);
Tel.: +86-20-6164-8530 (S.L.); +86-20-6278-9464 (B.X.)
† These authors contributed equally to this work.
ꢀꢁꢂꢀꢃꢄꢅꢆꢇ
ꢀꢁꢂꢃꢄꢅꢆ
Received: 31 July 2018; Accepted: 6 September 2018; Published: 12 September 2018
Abstract: A versatile and practical “on-water” protocol was newly developed to synthesize
quinazolinones using o-bromobenzonitrile as a novel starting material. Studies have found
that air as well as water plays an important role in synthesis of quinazolinones. Further
investigation indicated that dihydroquinazolinones can be prepared with this protocol under
the protection of N2. The protocol can be extended to other substrates and various
quinazolinones and dihydroquinazolinones were obtained. o-Bromobenzamide, o-aminobenzonitrile,
and o-aminobenzamide were also evaluated as starting materials, and the results further proved the
versatility of this protocol, especially towards dihydroquinazolinones.
Keywords: quinazolinones; dihydroquinazolinones; “on-water” reaction; selective synthesis
1. Introduction
Quinazolinones and dihydroquinazolinons are important classes of nitrogen-containing
heterocycles with an array of biological activities such an antitumor [
antibacterial [ ], anticonvulsant [ ], etc. As explicit examples, RVX-208 and balaglitazone, structurally
based on quinazolin-4(3H)-one (Figure 1), are now under phase III clinical trials. The compound of
RVX-208 is developed for the treatment of cardiovascular diseases and lipid metabolism disorders [ ],
while balaglitazone is developed for the treatment of type 2 diabetes [ ]. Recently, RVX-208 was found
], which stimulated our interest to synthesize the
1,2], anti-inflammatory [3],
4,
5
6
7
8
effective to reactivate HIV-1 in latent reservoirs [
9
compounds bearing a quinazolione core.
Figure 1. Structures of RVX-208 and balaglitazone.
Molecules 2018, 23, 2325; doi:10.3390/molecules23092325
www.mdpi.com/journal/molecules

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A variety of convenient methodologies have been developed for the synthesis of
quinazolinones [10 13]. o-Aminobenzamides [14 22] and o-bromobenzamides [12 23 31] are the
most frequently used starting materials by far, and o-Aminobenzoic acid [32], o-haloaniline [26 33],
and isatoic anhydride [34] were also introduced. Alternatively, o-aminobenzonitrile [35 37] was
–
–
, –
,
–
applied to prepare quinazolinones by Wu and co-workers [35], considering that the variation of
o-aminobenzonitriles is much more available than o-aminobenzamides. Similarly, o-bromobenzonitriles
can also be transformed into o-bromobenzamides in situ, and as mentioned above, o-bromobenzamide
is one of the most studied starting materials (Scheme 1) to synthesize quinazolinones. From a
synthetic point of view, we strived to explore o-bromobenzonitriles as an alternative substrate to
access quinazolinones for following reasons: (1) with o-bromobenzonitrile as an alternative starting
material, the scope of substrates could be substantially extended, and thus increase the variety of
quinazolinones; (2) in our methodology, transforming o-bromobenzonitrile into quinazolinones in
one pot can save an extra step (benzonitrile into benzamide [38,39] thus the cost can be reduced;
and (3) to the best of our knowledge, the substituted o-bromobenzonitriles were usually cheaper than
the corresponding o-bromobenzamides.
Scheme 1. In situ transformation from o-bromobenzamide to o-bromobenzamide.
Meanwhile, most of these reactions using DMSO or DMA as solvent, suffered from unpleasant
smells in high temperature. In addition, it is hard to remove solvent after the reaction. Langer and
co-workers [36] provided a green protocol so that dihydroquinazolinons can be prepared in H2O
with good yields, whereas quinazolinones can only be obtained by adding oxidant TBHP(tert-butyl
hydroperoxide). In the context of green chemistry, water was widely explored as a solvent in
various reactions [40
features, but also because the theoretical and practical advantages of water substantially improved the
“on-water” reaction [44 46]. To date, water has never been used as media to synthesize quinazolinones
–43], not only due to its low cost, non-toxicity, easy availability, and eco-benign
–
directly without adding any oxidant. Cognizant of these challenges, we tried to introduce water as
reaction media into the synthesis of quinazolinones. To our delight, we finally explored a versatile
and practical “on-water” protocol for the quinazolinone preparation from o-bromobenzonitriles with
comparable yields. Surprisingly, with this protocol, a dihydroquinazolinone skeleton could also be
built just under the protection of N2. Finally, we successfully synthesized 31 compounds including
quinazolinones and dihydroquinazolinons, and 10 (4aa, 4ee, 4eq, 4ff, 5aa, 5ea, 5eb, 5ee, 5eq, 5fe) of
them were novel compounds. Herein, we would like to present our research towards quinazolinones
synthesis in detail.
2. Discussion and Results
Preliminary investigation started with the reaction of o-bromobenzonitrile 1a (instead of
◦
o-bromobenzamide) [27], benzaldehyde
2
and ammonia
3
under 100 C in the present of CuBr,
L-proline, and Cs2CO3 for 24 h. The expected product 2-phenylquinazolin-4(3H)-one 4aa was obtained
(Entry 1, Table 1). The reaction conditions could further be optimized. The results collected in Table 1
showed that the reaction performed under 100 ◦C using Cs2CO3 as a base provided the highest yield
(Entries 1–8, Table 1). The further screening of the catalyst (Entries 9–15, Table 1) showed that copper
(Cu (II)) salts gave higher yields of product 4aa (Entries 12 and 14, Table 1) than Cu (I) in this case,
being totally different from the reported results [11,12,25,29,31].
With the catalyst CuCl2, solvent effects were examined (Entries 16–21, Table 1) and H2O was
successfully introduced. Without any oxidant, the “on-water” reaction provided compound 4aa with
yield of 75% (Entry 18, Table 1), much higher than using DMF and DMA media. Further attempts to

Molecules 2018, 23, 2325
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increase the yield by adding DMSO or PEG (polyethylene glycol) in water as a co-solvent failed (Entries
19–20, Table 1). Additionally, air was found to be important for the fusion of quinazolinone core,
as only traces of the product formed when the transformation was conducted under the protection of
N2 (Entry 22, Table 1). Based on these results, we can conclude that air and H2O are vital to promote the
formation of quinazolinone. Therefore, we obtained the optimal reaction conditions (CuCl2 (0.1 mmol),
Cs2CO3 (2 mmol), L-proline (0.2 mmol), H2O (2 mL)) for the condensation of o-bromobenzonitriles,
aldehydes, and aqueous ammonia toward quinazolinones, which are highlighted in Table 1 (Entry 18).
Table 1. Conditional optimization for the condensation of o-bromobenzonitrile 1a with benzaldehyde
2a a.
◦
Temp ( C) Yield (%) b
Entry Catal. (10 mol %) Base (2 eqv.)
Solvent
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuCl
-
Cs2CO3
Cs2CO3
Cs2CO3
-
K2CO3
K3PO4
NaOH
Et3N
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMF
DMA
100
80
54
49
42
38
47
51
37
21
54
16
33
62
28
63
45
24
41
120
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
CuI
CuCl2
FeCl3
CuO
ZnCl2
CuCl2
CuCl2
CuCl2
CuCl2
CuCl2
CuCl2
CuCl2
H2O
75
47
55
H2O/DMSO (4:1)
H2O/PEG400 (4:1)
DMSO
67
H2O
Trace c
a
Reaction conditions: o-bromobenzonitrile 1a (1 mmol), benzaldehyde 2a (2 mmol), aqueous ammonia
3 (27%,
1 mL), catalyst (0.1 mmol), base (2 mmol), L-proline (0.2 mmol), and solvent (2 mL), heated, sealed, and stirred for
b
c
12 h, then refluxed under air for 12 h. Isolated yield. Reaction was conducted under protection of N2.
With such an eco-friendly protocol in hand, the workup procedure was simple on account of
water. Thereupon, it is necessary to investigate the scope and limitation to explore the versatility of
this protocol. Before that, other o-halobenzonitriles (Entries 2–4, Table 2) were tested and the results
collected in Table 2 showed that o-bromobenzonitrile is the most active substrate for this reaction.
Various aryl aldehydes 2 were firstly evaluated under standard reaction conditions (Table 2). Generally,
most of them were well tolerated and successfully transformed into the corresponding products with
moderate to good yields. The electro-donating groups (-Me, -OMe) made a positive influence for the
reaction and resulted in higher yields (4ad
, 4ae, 4af, Table 2) than electro-withdrawing counterparts
(
4ab 4ac 4ai, Table 2). It is noteworthy that almost no steric effect was observed for benzaldehyde,
,
,
and o-methoxybenzaldehyde 2f even gave a higher yield up to 83% (4af, Table 2) than p-methoxyone
(4ae, Table 2). Then we extended this protocol to substituted o-bromobenzonitriles.

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The electro-withdrawing group on o-bromobenzonitrile (Entries 20–23, Table 2) was beneficial
to the transformation and gave higher yields of corresponding products than those electro-donating
group on o-bromobenzonitrile (Entries 24–28, Table 2). Therefore, we got an excellent yield of 92%
(4ef, Table 2) when 2-bromo-5-fluorobenzonitrile reacted with 2-methoxylbenzaldehyde, which further
proved that electro-donating benzaldehydes, especially 2-methoxylbenzaldehyde, were more active
than electro-withdrawing benzaldehydes.
Table 2. The scope and limitation for the synthesis of 2-aryl quinazolin-4(3H)-one 4 a.
Entry
X
R1
R2
Product Yield b
1
2
3
4
5
6
7
8
Br
F
Cl
I
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
C6H5
C6H5
C6H5
C6H5
4-ClC6H5
4aa
4aa
4aa
4aa
4ab
4ac
4ad
4ae
4af
4ag
4ah
4ai
4aj
4ak
4al
4am
4an
4ao
4ap
4ea
4ee
4ef
4eq
4fa
4fb
4fe
75%
0
21%
17%
44%
41%
71%
73%
83%
42%
0
27%
30%
66%
48%
0
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
2-ClC6H5
4-CH3C6H5
4-MeOC6H5
2-MeOC6H5
4-HOC6H5
2-HOC6H5
4-CF3C6H5
4-N(CH3)2C6H5
naphthalene
4-Pyridine
2-Pyridine
2-furan
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
0
0
-
-
2-thiophene
2-pyrrole
27%
60%
73%
92%
60%
63%
47%
51%
62%
67%
5-F
5-F
5-F
5-F
C6H5
4-MeOC6H5
2-MeOC6H5
3-MeO-4-HOC6H5
C6H5
Br 5-CH3
Br 5-CH3
Br 5-CH3
Br 5-CH3
Br 5-MeO
4-ClC6H5
4-MeOC6H5
2-MeOC6H5
4-MeOC6H5
4ff
4ge
a
Reaction conditions: substituted o-halobenzonitrile
1
(1 mmol), aryl aldehyde
2
(2 mmol), aqueous ammonia 3
(27%, 1 mL), CuCl2 (0.1 mmol), Cs2CO3 (2 mmol), L-proline (0.2 mmol), and H2O (2 mL), heated, sealed, and stirred
b
for 12 h, then refluxed under air for 12 h. Isolated yield.
Meanwhile, dihydroquinazolinones
We then repeated the model reaction under the protection of N2 (Entry 22, Table 1), after
which it failed to produce the compound 4aa 2,3-Dihydro-2-phenylquinazolin-4(1H)-one 5aa
was obtained and yielded 74%. This discovery suggested that 2-arylquinazolin-4(3H)-one and
5 were isolated as the side products in these reactions.
.
4
2,3-dihydro-2-arylquinazolin-4(1H)-one 5 can be selectively prepared from o-bromobenzonitrile by
controlling the air.
With this result, other substituted benzaldehydes were subsequently employed to prepare
2,3-dihydro-2-arylquinazolin-4(1H)-ones
5
.
The selected substituted benzaldehydes were
smoothly transformed into corresponding expected products with good to excellent yields

Molecules 2018, 23, 2325
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(Table 3). Unexpectedly, an opposite result was observed compared to the synthesis of
2-arylquinazolin-4(3H)-ones The electro-withdrawing group (4-Cl) helped to improve the
yield up to 96% (5ab), while the electro-donated group substituted benzaldehyde gave relatively
lower yields (5ae 5af, Table 3). Especially, o-methoxylbenzaldehyde 2f, which have provided
4.
,
2-(2-methoxyphenyl)quinazolin-4(3H)-one 4af in high yield up to 83%, resulted in the lowest
yield of 2,3-dihydro-2-(2-methoxyphenyl)-quinazolin-4(1H)-one 5af (54%) under N2 in this case.
This interesting observation partially manifested that the electron-rich benzaldehyde is good
to form 2-arylquinazolin-4(3H)-ones 4, while electron-deficient benzaldehyde tends to produce
2,3-dihydro-2-aryl quinazolin-4(1H)-ones 5.
Therefore, 2-bromo-5-fluorobenzonitrile as well as 2-bromo-5-methylbenzonitrile was treated
with benzaldehydes and aqueous ammonia under the the protection of N2 with standard reaction
conditions (5ea–5fe, Table 3). Most of them were smoothly transformed into the expected dihydroxyl-
products in good yields.
Table 3. The scope and limitation for the synthesis of 2,3-dihydro-2-aryl quinazolin-4(1H)-one 5 a.
Entry
R1
R2
Product Yield b
1
2
3
4
5
6
7
8
9
-
-
-
C6H5
5aa
5ab
5ae
5af
5ea
5eb
5ee
5eq
5fa
5fb
5fe
74%
96%
71%
54%
39%
27%
53%
53%
77%
0
4-ClC6H5
4-MeOC6H5
2-MeOC6H5
C6H5
4-ClC6H5
4-MeOC6H5
2-MeOC6H5
C6H5
-
5-F
5-F
5-F
5-F
5-CH3
5-CH3
10
11
4-ClC6H5
5-CH3 4-MeOC6H5
50%
a
Reaction conditions: substituted o-bromobenzonitrile 1a (1 mmol), aryl aldehyde
2 (2 mmol), aqueous ammonia 3
(27%, 1 mL), CuCl2 (0.1 mmol), Cs2CO3 (2 mmol), L-proline (0.2 mmol), and H2O (2 mL), heated, sealed, and stirred
b
under protection of N2 for 24 h. Isolated yield.
According to the results and similar reactions [12,13,24,32], a possible mechanism was proposed
and outlined in Scheme 2. In the presence of Cs2CO3, the coordination of L-proline with CuCl2
helped to promote the subsequent Ullmann-type reaction to form 2-amino, while oxidation from -CN
to -CONH2 occurred simultaneously in the presence of CuCl2, base, and H2O, so that intermediate
2-aminobenzamide was generated. Actually, 2-aminobenzamide was detected as intermediate during
the reaction, andthen condensation and addition occurred on 2-aminobenzamide and benzaldehyde.
2,3-Dihydro-2-aryl quinazolin-4(1H)-one 5 was produced under the protection of N2, and when the
reaction was exposed to air after the starting materials were stirred in sealed tubes at 100 ◦C for 12 h,
oxidation occurred further to afford products 2-aryl quinazolin-4(3H)-one 4.

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Cu
H
OH
O
H
N
N
Cs2CO3/H2O
CsCl
O
CuCl2
+
O
CuCl2
CuCl2
H
N
H
N
O
H
Cs2CO3
CN
Cs2CO3
CuCl2
NH3, H2O
Cu
OH
Br
NH2
H
N
Br
Cu
H
OH
O
Cu NH2
Br
O
H
N
O
N
O
O
O
NH
O
N
H
N2
CHO
O
N
O
5
Cs2CO3
NH2
NH2
Addition
Oxidation
air [O]
H2O
Condensation
Cu(II)
HBr
NH2
NH
N
4
Scheme 2. Proposed mechanism.
Although at the outset of this work we only expected to develop an “on-water” protocol
towards quinazolinones from o-bromobenzonitrile 1a, the explicit outcome above proved the
versatility of this protocol. Then other commonly used substrates were evaluated for this protocol.
o-Bromobenzamide 1h was first reacted with p-methoxylbenzaldehyde and ammonia under the
standard conditions. As outlined in Scheme 3, 2-(4-methoxyphenyl)-quinazolin-4(3H)-one 4ae and
2,3-dihydro-2-phenylquinazolin-4(1H)-one 5ae were produced smoothly at 74% and 68%, respectively,
almost having the same yields with o-bromobenzonitrile (73% for 4ae in Table 2, and 71% for 5ae in
Table 3).
Scheme 3. The “on-water” reaction starting from o-bromobenzamide.
Subsequently, o-aminobenzonitrile 1i was tested and the results in Scheme 4 showed that
the yield of 2-phenylquinazolin-4(3H)-one 4aa was only 43%, while o-bromobenzonitrile 1a
yielded in 75% (4aa, Table 2). But, when under the protection of N2, 76% of the yield of
2,3-dihydro-2-phenylquinazolin-4(1H)-one 5aa was obtained, almost the same with the result

Molecules 2018, 23, 2325
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from o-bromobenzonitrile 1a
(
5aa, Table 3). Obviously, o-aminobenzonitrile 1i was less active
than o-bromobenzonitrile 1a for the synthesis of quinazolin-4(3H)-one, which explained why
2,3-dihydro-quinazolin-4(1H)-ones were the only products listed in the literature reported by Langer
and co-workers [36], wherein oxidant TBHP had to be added in addition to help the formation of
quinazolin-4(3H)-one.
Scheme 4. The “on-water” reaction starting from o-aminobenzanitrile.
This interesting finding prompted us to undertake the reaction starting from o-aminobenzamide
1j immediately, as shown in Scheme 5. Unexpectedly, oxidized product 2-phenylquinazolin-4(3H)-one
4aa failed to produce, while 2,3-dihydro-2-phenylquinazolin-4(1H)-one 5aa yielded up to 95%
without the protection of N2. It implies that o-aminobenzamide 1j tends to be transformed into
2,3-dihydro-quinazolin-4(1H)-ones 5 with this protocol.
Scheme 5. “On-water” reaction starting from o-aminobenzamide.
With these results from the extended substrates, we found the newly developed “on-water”
protocol was much more flexible for the construction of 2,3-dihydro-quinazolin-4(1H)-ones 5 than its
oxidized products quinazolin-4(3H)-ones
, the priority of the commonly used substrates is: o-bromobenzonitrile 1a or o-bromobenzamide 1h
o-amino- benzonitrile 1i > o-aminobenzamide 1j.
4. In addition, for the preparation of quinazolin-4(3H)-ones
4
>

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3. Conclusions
In summary, we have newly developed a versatile and practical “on-water” protocol towards
compounds containing a quinazolinone core, and o-bromobenzonitrile was explored as an alternative
starting material. Water and air were found to be of importance for the formation of oxidized
products quinazolin-4(3H)-ones
o-bromobenzonitriles were successfully applied to this protocol and provided the expected
quinazolin-4(3H)-ones . Moreover, we found that 2,3-dihydro-quinazolin-4(1H)-ones could also
be obtained when the reaction was carried out under the protection of N2, and the subsequent scope
investigation resulted in the successful synthesis of various 2,3-dihydro-quinazolin-4(1H)-ones
Therefore, we can selectively produce the compounds 2,3-dihydro-quinazolin-4(1H)-ones or their
oxidized products from o-bromobenzonitrile by controlling air. In addition, o-bromobenzonitrile,
o-aminobenzonitrile, and o-aminobenzamide were evaluated and all of them could be transformed
into 2,3-dihydro-quinazolin-4(1H)-ones with good to excellent yields, but o-bromobenzonitrile or
4, and various aryl aldehydes as well as several substituted
4
5
5.
5
4
5
o-bromobenzamide was proved to be the best substrate for the synthesis of the oxidized products
quinazolin-4(3H)-ones compared with o-aminobenzonitrile and o-aminobenzamide. With these new
findings in mind, further work involving the synthesis of RVX-208 and related structural modifications
are ongoing in our group.
4. Materials and Methods
4.1. General
All chemicals were purchased from commercial suppliers Shanghai Energy Chemical Co., Ltd.
(Shanghai, China), Adamas Reagent, Ltd. (Shanghai, China), TCI Industry Co., Ltd. (Shanghai, China),
without further purification. All reactions were monitored by TLC (thin-layer chromatography)
which was performed on GF254 silica gel glass plates (Qingdao Haiyang Chemical Co. Ltd.,
Qingdao, Shandong, China). Column chromatography was performed with silica gel (200–300
mesh). All unknown compounds were structurally verified by 1H-NMR, 13C-NMR and MS, and 1H-,
and 13C-NMR spectra were recorded on a Bruker Advance drx 400 spectrometer (Bruker Bioscience,
Billerica, MA, USA) operating at 400 MHz and 100 MHz, respectively. The chemical shifts were
reported in ppm and the coupling constant in Hz. Mass Spectrometry analysed for the known
compounds by Waters HPLC/ZQ 4000 Thermo Fisher Scientific (Waltham, MA, USA).
4.2. General Procedure for the Synthesis of 2-Phenylquinazolin-4(3H)-one (4aa)
To a mixture of 2-Bromobenzonitrile (183.4 mg, 1 mmol), benzaldehyde (210.5 mg, 2 mmol),
CuCl2 (17.2 mg, 0.1 mmol), Cs2CO3 (652.2 mg, 2 mmol), and L-proline (23.2 mg, 0.2 mmol) in H2O
(2 mL) was added 27% aqueous ammonia (1 mL) in a tube under air atmosphere. Then the tube
was sealed, and the mixture was stirred at 100 ◦C for 12 h. Next, the tube was opened to air and the
mixture was stirred at 100 ◦C for another 12 h. After being cooled to room temperature, the resulting
mixture was quenched with NH4Cl solution and extracted with ethyl acetate. The combined organic
layer was washed with brine, and then dried over anhydrous Na2SO4. The solvent was evaporated
under reduced pressure and the crude product was purified by chromatography on silica-gel to afford
1
2-phenylquinazolin-4(3H)-one (4aa) in 75% isolated yield. H-NMR (400 MHz, Chloroform-d)
δ
11.24
(s, 1H, -NH-), 8.27 (d, J = 7.8 Hz, 1H, Ar-H), 8.16 (dd, J = 6.6, 3.0 Hz, 2H, Ar-H), 7.82–7.71 (m, 2H,
Ar-H), 7.57–7.49 (m, 3H, Ar-H), 7.48–7.41 (m, 1H, Ar-H). 13C-NMR (100 MHz, Chloroform-d)
δ151.60,
134.87, 132.77, 131.64, 129.05, 127.97, 127.25, 126.79, 126.34, 120.84. HRMS (ESI) calcd for C14H11N2O
[M + H]+: 223.0866. Found: 223.0865.
4.3. General Procedure for the Synthesis of 2-Phenyl-2,3-dihydroquinazolin-4(1H)-one (5aa)
2-bromobenzonitrile (182.3 mg, 1 mmol), benzaldehyde (213.6 mg, 2 mmol), CuCl2 (17.1 mg,
0.1 mmol), Cs2CO3 (651.3 mg, 2 mmol) and L-proline 23.4 mg, 0.2 mmol) in H2O (2 mL) were added

Molecules 2018, 23, 2325
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into a tube and stirred. Remove the air inside the tube under the reduced pressure and flush with N2,
and protected the starting materials under N2. 27 % aqueous ammonia (1 mL) was added into the
reaction mixture. The tube was then sealed and the mixture stirred at 100 ◦C for 24 h. After cooling
to room temperature, the resulting mixture was quenched with NH4Cl solution and extracted with
ethyl acetate. The combined organic layers were washed with brine and then dried over anhydrous
Na2SO4. The solvent was evaporated under reduced pressure and the crude product was purified by
chromatography on silica-gel to afford 2-phenyl-2,3-dihydroquinazolin-4(1H)-one(5aa) in 74% isolated
1
yield. H-NMR (400 MHz, Chloroform-d)
δ 7.97 (d, J = 7.8 Hz, 1H, Ar-H), 7.67–7.56 (m, 2H, Ar-H),
7.55–7.41 (m, 3H, Ar-H), 7.36 (t, J = 7.7 Hz, 1H, Ar-H), 6.93 (t, J = 7.5 Hz, 1H, Ar-H), 6.70 (d, J = 8.0 Hz,
1H, Ar-H), 5.93 (s, 1H, -CH-), 5.80 (s, 1H, -NH-), 4.42 (s, 1H, -NH-). 13C-NMR (101 MHz, DMSO)
δ
163.98, 148.27, 142.04, 133.70, 128.85, 128.72, 127.75, 127.26, 117.51, 115.36, 114.80, 66.96. HRMS (ESI)
calcd for C14H13N2O [M + H]+: 225.1022. Found: 225.1021.
4.4. General Procedure for the Synthesis of 2-Phenylquinazolin-4(3H)-one (4aa) with Scheme 3
o-Aminobenzanitrile (119.8 mg, 1 mmol), benzaldehyde (217.8 mg, 2 mmol), CuCl2 (17.6 mg,
0.1 mmol), Cs2CO3 (652.3 mg, 2 mmol), and L-proline 23.6 mg, 0.2 mmol) in H2O (2 mL) was added
◦
in a 5 mL reaction bottle. Then the mixture was stirred at 100 C for 48 h. After cooling to room
temperature, the resulting mixture was quenched with NH4Cl solution and extracted with ethyl
acetate. The combined organic layers were washed with brine and then dried over anhydrous
Na2SO4. The solvent was evaporated under reduced pressure and the crude product was purified by
chromatography on silica-gel to afford 2-phenylquinazolin-4(3H)-one (4aa) in 43% isolated yield.
4.5. General Procedure for the Synthesis of 2-Phenyl-2,3-dihydroquinazolin-4(1H)-one (5aa) with Scheme 3
o-Aminobenzanitrile (120.8 mg, 1 mmol), benzaldehyde (216.7 mg, 2 mmol), CuCl2 (17.3 mg,
0.1 mmol), Cs2CO3 (653.7 mg, 2 mmol), and L-proline 23.3 mg, 0.2 mmol) in H2O (2 mL) was added in
a 5 mL reaction bottle under nitrogen. Then the mixture was stirred at 100 ◦C for 24 h. After cooling
to room temperature, the resulting mixture was quenched with NH4Cl solution and extracted with
ethyl acetate. The combined organic layers were washed with brine and then dried over anhydrous
Na2SO4. The solvent was evaporated under reduced pressure and the crude product was purified
by chromatography on silica-gel to afford 2-phenyl-2,3-dihydroquinazolin-4(1H)-one (5aa) in 76%
isolated yield.
4.6. General Procedure for the Synthesis of 2-Phenyl-2,3-dihydroquinazolin-4(1H)-one (5aa) with Scheme 4
o-Aminobenzamide (139.1 mg, 1 mmol), benzaldehyde (209.9 mg, 2 mmol), CuCl2 (17.6 mg,
0.1 mmol), Cs2CO3 (657.0 mg, 2 mmol) and L-proline 23.6 mg, 0.2 mmol) in H2O (2 mL) was added
◦
in a 5 mL reaction bottle. Then the mixture was stirred at 100 C for 14 h. After cooling to room
temperature, the resulting mixture was quenched with NH4Cl solution and extracted with ethyl
acetate. The combined organic layers were washed with brine and then dried over anhydrous
Na2SO4. The solvent was evaporated under reduced pressure and the crude product was purified
by chromatography on silica-gel to afford 2-phenyl-2,3-dihydroquinazolin-4(1H)-one (5aa) in 95%
isolated yield.
Experimental procedures and analytical data of all compounds (1H NMR and 13C NMR), copy of
the 1H NMR and 13C NMR and data are available in the Supplementary Materials.
Supplementary Materials: The experiment procedure, spectral and analytical data, characterization data
including 1H-, 13C-, and 19F-NMR spectra of compounds 1–31 are available online.
Author Contributions: B.X. and S.L. conceived and designed the study; Z.L., L.-Y.Z., C.L., F.Y. and F.Q. performed
the experiments; all author analyzed the data; all authors contributed to writing and editing the paper.
Funding: This research was funded Guangdong Science and Technology Department of China [2013B051000056].

Molecules 2018, 23, 2325
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Acknowledgments: We thank the Guangdong Science and Technology Department of China (2013B051000056)
for financial support.
Conflicts of Interest: The authors declare no conflict of interest.
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Sample Availability: Samples of the compounds are not available from the authors.
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2018 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access
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